For example, articular cartilage is hyaline cartridge that is composed of a small number of cells, collagenous extracellular matrix, abundant proteoglycans and water. In the case of bone, since vascular and neural networks are present and bone has the ability to self-repair, even if a fracture has occurred, the fracture is frequently completely repaired. However, articular cartilage lacks vascular and neural networks. Consequently, it has virtually no potential for self-repair, and in the case of the formation of large cartilage defects in particular, the cartilage defect is not adequately repaired. Even at those portions that are repaired, fibrous cartilage is formed that has different mechanical properties than hyaline cartilage. Consequently, when a cartilage defect is formed, joint pain and loss of function are brought about that frequently progress to osteoarthritis. In addition, a cartilage defect can reach over a broad range as a result of symptoms progressing from the initial stages of osteoarthritis that began with wear of the surface of articular cartilage due to aging or excessive joint usage.
Although osteoarthritis (OA) is a degenerative disease in which articular cartilage is worn down due to aging and excessive joint use, in addition to the mechanical cause of wear, local inflammatory responses, such as the production of inflammatory cytokines by synovial cells and chondrocytes and the induction of algesic substances and proteases by inflammatory cytokines, are also said to be involved in joint destruction. Namely, accompanying wear of articular cartilage (mechanical damage), an inflammatory response is induced within joint tissue, self-destructive cartilage damage progresses due to this inflammatory response and mechanical damage further progresses due to decreased joint function, thereby resulting in a vicious cycle that further exacerbates the disease. Treatment of osteoarthritis focuses primarily on the removal of pain and inflammation at the affected area, and is commonly treated overseas with administration of non-steroid anti-inflammatory drugs. However, since renal function may be depressed in elderly patients, continuous oral administration of non-steroid anti-inflammatory drugs may be difficult from the viewpoint of safety. Products incorporating hyaluronic acid, which is a component of cartilage synovial fluid, improve the lubricating function of joints by being administered into a joint, and since these products also having analgesic action, they are widely used as joint function improving agents for osteoarthritis. However, in severe cases of osteoarthritis associated with advanced degeneration of cartilage and surrounding tissue, there is ultimately no other choice but to replace the joint with an artificial joint, thus making this one of the diseases for which there is a need to develop a novel therapeutic drug that inhibits and ultimately improves the advance of tissue degeneration (Reference 1).
Although the mechanism of occurrence of rheumatoid arthritis (RA) is not fully understood, it has been reported to involve inflammation and abnormal growth of the synovial membrane and an excessive immune response mediated by activated T-cells, resulting in progressive destruction of joint tissue. Although RA demonstrates symptoms resembling OA with respect to being associated with degeneration of joint tissue, RA is a type of autoimmune disease, and has a different pathology from that of OA. Recently, biological preparations have come to be used as RA therapeutic drugs targeted at an inflammatory cytokine in the form of TNF-α. These preparations have as active ingredients thereof anti-TNF-α antibodies or TNF receptors, and are thought to contribute to prevention of joint destruction by inhibiting the function of TNF-α. On the other hand, since these preparations inhibit the function of TNF-α systemically, serious adverse effects, including infectious diseases such as pneumonia and tuberculosis, present problems clinically. Thus, there is a need for a novel therapeutic drug that is highly safe and capable of inhibiting the progression of joint tissue degeneration.
Alginic acid is high molecular weight polysaccharide present in large amounts in brown algae that is a polymer obtained by linearly polymerizing two types of uronic acids in the form of D-mannuronic acid (M) and L-gluronic acid (G). In addition to exhibiting viscosity when in solution, since alginic acid also has the property of gelling in the presence of a cation having a valence of 2 or more, it is widely used as a thickener or gelling agent in foods, cosmetics and base materials of pharmaceutical preparations. A technology has come to be used that utilizes this gelling property of alginic acid by which beads embedded with cells are produced by dropping an alginic acid solution with cells suspended therein into a calcium ion solution. Attempts have been made to embed chondrocytes and the like in such beads followed by transplanting to a cartilage injury lesions. Reference 2 provides a discussion indicating that alginic acid can be used as a carrier without having any disadvantageous affects whatsoever on the cartilage injury lesions, and that alginic acid per se does not have any therapeutic effects. In addition, Reference 3 discloses that, although normal cartilage tissue was formed in a graft following the suspension of chondrocytes in a sodium alginate solution, injecting into a rabbit cartilage defect and curing the surface with CaCl2 solution, fibrous cartilage is formed in the case of applying only alginic acid to the cartilage defect without containing cells therein. Reference 4 discloses a curable, self-gelling alginic acid composition, comprising a mixture of a soluble alginic acid salt and an insoluble alginic acid salt/gel, which contains chondrocytes and is injected into a cartilage defect.
In this manner, alginic acid is known to be a biopolymer capable of being used as a carrier of chondrocytes and the like, and has been attempted to be used as a transplant carrier that is injected into a cartilage defect together with cells and then cured by taking advantage of its gelling ability. However, the therapeutic effects of an alginic acid composition not containing cells are unknown, and the application of a non-curing alginic acid composition to joint disease has yet to be attempted.
[References]
    1. Harumoto Yamada et al., “Drug therapy for osteoarthritis”, Clin. Rheumatol., Vol. 18, 2006: pp. 298-306    2. Cay M. Mierisch et al., “Transforming Growth Factor-β in Calcium Alginate Beads for the Treatment of Articular Cartilage Defects in the Rabbit”, The Journal of Arthroscopic and Related Surgery, Vol. 18, No. 8 (October), 2002: pp. 892-900    3. E. Fragonas et al., “Articular Cartilage Repair in Rabbits by Using Suspensions of Allogenic Chondrocytes in Alginate”, Biomaterials, Vol. 21, 2000: pp. 795-801    4. International Publication WO 2006/044342